5-1880777-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016358.3(IRX4):c.355G>A(p.Ala119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,613,276 control chromosomes in the GnomAD database, including 30,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3015 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27362 hom.)
• Consequence: IRX4 NM_016358.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.73

Genes affected

IRX4 (HGNC:6129): (iroquois homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell development; neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within heart development. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017234981).
• BP6: Variant 5-1880777-C-T is Benign according to our data. Variant chr5-1880777-C-T is described in ClinVar as [Benign]. Clinvar id is 1280723.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRX4	NM_016358.3	c.355G>A	p.Ala119Thr	missense_variant	3/5	ENST00000231357.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX4	ENST00000231357.7	c.355G>A	p.Ala119Thr	missense_variant	3/5	1	NM_016358.3	P1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29502 AN: 151854 Hom.: 3001 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.00600

Gnomad SAS AF: 0.0862

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.167 AC: 41884 AN: 251104 Hom.: 4141 AF XY: 0.166 AC XY: 22597 AN XY: 135812

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.00729

Gnomad SAS exome AF: 0.0964

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.188 AC: 274538 AN: 1461306 Hom.: 27362 Cov.: 33 AF XY: 0.185 AC XY: 134771 AN XY: 726986

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.289

Gnomad4 EAS exome AF: 0.00715

Gnomad4 SAS exome AF: 0.0967

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.185

GnomAD4 genome AF: 0.194 AC: 29541 AN: 151970 Hom.: 3015 Cov.: 31 AF XY: 0.191 AC XY: 14221 AN XY: 74300

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.00601

Gnomad4 SAS AF: 0.0861

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.195

Alfa AF: 0.202 Hom.: 6808

Bravo AF: 0.194

TwinsUK AF: 0.187 AC: 693

ALSPAC AF: 0.189 AC: 727

ESP6500AA AF: 0.230 AC: 1014

ESP6500EA AF: 0.203 AC: 1742

ExAC AF: 0.166 AC: 20105

Asia WGS AF: 0.0650 AC: 226 AN: 3478

EpiCase AF: 0.216

EpiControl AF: 0.212

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Benign	0.79
DEOGEN2	Benign	0.070	T;T;.;.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.76	D
MetaRNN	Benign	0.0017	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;N;N;N;N;.
MutationTaster	Benign	0.15	P;P;P
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.040	N;N;.;.;N;N
REVEL	Benign	0.074
Sift	Benign	0.58	T;T;.;.;T;T
Sift4G	Benign	0.45	T;T;T;T;T;T
Polyphen		0.58	P;P;.;.;P;.
Vest4		0.31
MPC		0.59
ClinPred		0.013	T
GERP RS		4.0
Varity_R		0.093
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2232376; hg19: chr5-1880891;